Are there any guidelines for clinical trials of medical devices?

Bhaskar In August 2010, CDSCO had released guidance document on requirements for conducting clinical trials of medical devices. The requirements are similar to drugs. The application should include: 1) Covering letter, 2) Form 44, 3) Fee in TR6 challan, 4) Delegation of responsibility, 5) Protocol, 6) Global regulatory status of the device, 7) Investigators undertaking, 8) Ethics committee approval, 9) Informed consent form, 10) Case record form, 11) Patient record form, 12) Relevant published literature, 13) Investigators brochure, 14) Suspected unexpected serious adverse reaction (SUSAR), 15) Affidavit from the sponsor, 16) Any other specific relevant information, 17) Clinical study report, if any. There are several annexures to be appended to the application. Some of these are standard e.g. protocol, SAE reporting form etc. However, there are some annexures which require specific details of the device. Annexure I form 44 covers particulars of subject device e.g. composition of device, specifications/standards of device, qualitative and quantitative particulars of the constituents, sterility and stability of the product, labeling details, risk classification (in country of origin as well as in 5 GHTF countries i.e. EU, USA, Japan, Canada, Australia), regulatory status of the subject device (particularly 5 GHTF countries i.e. EU, USA, Japan, Canada, Australia) Annexure II covers Technical Data and Annexure V describes Phase Study Assessment. If a global CT is going on and India being one of the countries, is it mandatory to submit the foreign SUSARs to the DCGI? Ashish Chavda Yes, Indian GCP and Schedule Y do not differentiate between local or foreign SAEs/SUSARs. See Below. Schedule Y (iv) Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the sponsor to the licensing authority and to the other investigator(s) participating in the study. Indian GCP 3.1.10. Safety Information: Sponsor is responsible for the ongoing safety evaluation of the product. The sponsor should promptly notify all concerned of findings that could adversely affect the safety of the subjects, impact the conduct of the Study or alter the Ethics Committees approval / favorable opinion to continue the Study. The Sponsor, together with Investigator(s), should take appropriate measures necessary to safeguard the study subjects. 3.1.11. Adverse Drug Reaction Reporting:

The Sponsor should provide ADR / AE reporting forms to the Investigator(s) / Institution(s). The sponsor should expedite the reporting to all concerned (including the Ethics Committee and the regulatory authorities) of all serious and/or unexpected adverse drug reactions In the Ethics Committee membership list two lawyers are present. One can act as legal expert and other one act as lay person. Is this right? Please clarify. Asif Dictionary defines lay person as a person who does not have specialized or professional knowledge of a subject. A lawyer is a specialist in law. Hence, a lawyer cannot be considered a lay person. If the quote A new drug shall continue to be considered as new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier is true does FDC having individual molecules in IP cease to exist as new drug? Anand P Please see definition of new drug under rule 122E. FDC is a separate category under new drug. The 4-yrs clause applies to a single drug not FDC. 122 E (c) A fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage, dosage form (including sustained release dosage form) and route of administration Do we need to take approval from the DCGI office for the research studies/ dissertations to be conducted on an old drug for a new indication? Dr Harsha M Shetty If a company is sponsoring the study with an objective of obtaining registration for additional indication, DCGI approval is needed. If you are conducting an Investigator initiated study for research purpose/dissertation, the requirements for regulatory approval is not clearly defined.

A trial patient visited the site complaining breathlessness and tachycardia. The investigator advised hospitalization but as subject could not afford the expenses, he refused for admission. Is this an SAE because investigator advised hospitalization? G Praveen Kumar. If the patient was not hospitalized, it does not fall into SAE criteria of hospitalization. However, it appears from your mail that the PI felt that the event was serious enough to admit the subject for treatment. This makes it an important medical event." As per ICH E2A such event also are considered serious. See the ICH E2A excerpt below: Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require

intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. There is also one more problem here. As per Indian GCP, and recent DCGI directive, the cost of medical treatment has to be covered by the sponsor. Hence, the PI should have treated the patient free of charge and recovered the cost from the sponsor. How often should the ICF be updated considering there are CIOMS generated on an ongoing basis during the course of a trial? Garima Singh As per ICH E6, section 4.8.2, the written ICF and any other written information provided to subjects should be revised whenever important new information becomes available that may be relevant to the subjects consent. It also states that the IRB/IEC, the subject or the LAR should be informed in a timely manner if new information becomes available that maybe relevant to the subjects willingness to continue participation in the trial. If the CIOMS contains information that is relevant to the subjects consent then the ICF needs to be updated. Also 21 CFR 50.25 (b) states that significant new findings developed during the course of research which may relate to the subjects willingness to continue participation will be provided to the subject. IB needs to be updated annually, but what if there are no safety updates in a particular year? Garima Singh As per ICH-GCP, the IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with GCP relevant new information may be so important that it should be communicated to the investigators, and possibly to the (IECs and/or regulatory authorities before it is included in a revised IB. Given this, the IB has to be revised annually even if there are no safety updates with a mention of the same. What are the labelling requirements for clinical trials in India? Dr Sunita Vashishtha The labelling for clinical trials is as per relevant GMP requirements. However, we accept the labels as per International labels for clinical trials. Indian GCP has given a format 2.3.1.6. Handling of the Product(s)

Measures to be implemented to ensure the safe handling and storage of the pharmaceutical products. System to be followed for labelling of the product(s) (code numbering etc.)

The label should necessarily contain the following information: the words - for clinical studies only, the name or a code number of the study, name and contact numbers of the investigator, name of the institution, subjects identification code.

However, name and contact numbers of the investigator is not given as this practically difficult. Kindly advise us whether we require DCGI or Ayush approval for conducting a postmarket clinical trial on an ayurvedic product. And please advise us whether it is mandatory to register such trials with CTRI. Ajay Jagan Ayush GCP guideline defines Phase IV as follows: Phase IV: Studies performed after marketing of the ASU medicine / other TM. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new ASU medicines / TM. ICMR 2006 recommends phase IV - The phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. It is an important aspect of drug trial on the long-term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee. There is a need to correlate the adverse events reported during phase IV trials with the toxicity data generated in animals, to draw markers for future warnings of potential adverse events likely to occur with other drugs. These trials may not be necessary for approval of new drug for marketing but may be required by the Licensing Authority for optimizing its use. These studies also include those on specific pharmacologic effect, drug-drug interaction(s), dose-response studies, trials designed to support use under approved indication(s) e.g. mortality/morbidity studies, clinical trials in a patient population not adequately studied in the pre-marketing phase, e.g., children; and epidemiological studies etc. Bioequivalence and bioavailability study also falls under this category. In addition there are phase IV studies that are designed to evaluate the marketed drug in specifically designed studies, which have inclusion/exclusion criteria, objectives and end points. The drug is used for the labelled indication in these studies. Therefore Licensing Authority permission is not needed. However, EC permission is needed. A third type of post-marketing study involves evaluation of the drug for a new indication of a

marketed drug, e.g. studies with letrazole. Here, DCGI permission and EC approval are needed which really makes the trial a Phase III study. If the objective of post-marketing clinical trial is to assess safety of the formulation, no regulatory approval is needed. However, if the study is a clinical trial in a new indication, regulatory permission is needed. For herbal products, the regulatory issues are reviewed by Department of Ayush. Kindly clarify how long the study documents will be archived

Mohammed Asif The requirements are as follows: EU Commission for at least 15 years after completion or discontinuation of the trial, or for at least two years after the granting of the last marketing authorization in the European Community and when there are no pending or contemplated marketing applications in the European Community, or for at least two years after formal discontinuation of clinical development of the investigational product. US FDA An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified With respect the expedited review by the ethics committee, what is the requirement for expedited review for the ethics committee? Rupa Indian GCP describes this under Interim Review whilst ICMR gives detail recommendation. The requirements of document submission will be as per Schedule Y Indian GCP 4.2.7. Interim Review The IEC should decide and record the special circumstances and the mechanism when an interim review can be resorted-to instead of waiting for the scheduled time of the meeting. However, decisions taken should be brought to the notice of the main committee. This can be done for the following reasons: i) re-examination of a proposal already examined by the IEC; ii) research study of a minor nature such as examination of case records etc.; iii) an urgent proposal of national interest.

ICMR 2006 2. Expedited Review The proposals presenting no more than minimal risk to research participants may be subjected to expedited review. The Member-Secretary and the Chairperson of the IEC or designated member of the Committee or Subcommittee of the IEC may do expedited review only if the protocols involve:1. Minor deviations from originally approved research during the period of approval (usually of one year duration). 2. Revised proposal previously approved through full review by the IEC or continuing review of approved proposals where there is no additional risk or activity is limited to data analysis. 3. Research activities that involve only procedures listed in one or more of the following categories: a. Clinical studies of drugs and medical devices only when i. research is on already approved drugs except when studying drug interaction or conducting trial on vulnerable population or ii. adverse event (AE) or unexpected adverse drug reaction (ADR) of minor nature is reported. 4. Research involving clinical materials (data, documents, records, or specimens) that have been collected for non-research (clinical) purposes. 5. When in emergency situations like serious outbreaks or disasters a full review of the research is not possible, prior written permission of IEC may be taken before use of the test intervention. Such research can only be approved for pilot study or preliminary work to study the safety and efficacy of the intervention and the same participants should not be included in the clinical trial that may be initiated later based on the findings of the pilot study. a. Research on interventions in emergency situation When proven prophylactic, diagnostic, and therapeutic methods do not exist or have been ineffective, physicians may use new intervention as investigational drug (IND) / devices/vaccine to provide emergency medical care to their patients in life threatening conditions. Research in such instance of medical care could be allowed in patients i. when consent of person/ patient/ responsible relative or custodian/ team of designated doctors for such an event is not possible. However, information about the intervention should be given to the relative/ legal guardian when available later; ii. when the intervention has undergone testing for safety prior to its use in emergency situations and sponsor has obtained prior approval of DCGI; iii. only if the local IEC reviews the protocol since institutional responsibility is of paramount importance in such instances. iv. if Data Safety Monitoring Board (DSMB) is constituted to review the data; b. Research on disaster management A disaster is the sudden occurrence of a calamitous event at any time resulting in substantial material damage, affecting persons, society, community or state(s). It may be periodic, caused by both nature and humans and creates an imbalance between the capacity and resources of the society and the needs of the survivors or the people whose lives are threatened, over a given period of time. It may also be unethical sometimes not to do research in such circumstances. Disasters create vulnerable persons and groups in society, particularly so in disadvantaged communities, and therefore, the following points need to be considered when reviewing such research: i. Research planned to be conducted after a disaster should be essential culturally sensitive and specific in nature with possible application in future disaster situations.

ii. Disaster-affected community participation before and during the research is essential and its representative or advocate must be identified. iii. Extra care must be taken to protect the privacy and confidentiality of participants and communities. iv. Protection must be ensured so that only minimal additional risk is imposed. v. The research undertaken should provide direct or indirect benefits to the participants, the disaster-affected community or future disaster-affected population and a priori agreement should be reached on this, whenever possible, between the community and the researcher. vi. All international collaborative research in the disaster-affected area should be done with a local partner on equal partnership basis. vii. Transfer of biological material, if any, should be as per Government rules taking care of intellectual property rights issues. I am writing this seeking your help on resolving an issue related to change of PI. PI of a running trial wishes to relinquish his role and has suggested another investigator. Later it was found that the suggested PI is the member of EC who was present in some of the meetings where some of the documents ( Protocol amendments and revised ICFs) related to this study were reviewed. However, the suggested PI was absent when the study was first submitted and was given conditional approval. Would this become a finding? Gajjela Praveen It appears that the new PI is a member of EC. However, when the protocol was reviewed by EC, he was not a PI. Hence, there was no conflict of interest for him at that time. He could take part in discussions and could vote as he was not the PI. For a trial to be conducted in India, support marketing in US/Europe, whose approval is required? Which guideline should be followed? Naveen MR For trial to support marketing in US/Europe, you have to conduct multi country trial with India as one of the countries. The IND approval has to be taken from the US/European authorities for the global trial and from DCGI in India. The trial has to comply with regulations in US/Europe, ICH-GCP, Schedule Y and Indian GCP. We know that D&C Act 1940 states that drugs should be dispensed by a registered pharmacist. However, all Indian sites do not have pharmacists available. Most of the time, dispensing of drugs (oral tablets, strips) are being done by study coordinators (who may or may not be a registered pharmacists). How can one manage this situation? Rohit Prasad Indian / ICH GCP does not mandate requirement of a pharmacist at the site. (See below). The person who is assigned the task has to be knowledgeable about the IP as required by the protocol, regulations GCP and GMP. ICH GCP 4.6.2 - Where allowed/required, the investigator/institution may/should assign some

or all of the investigator's/institutions duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.. 4.6.3 - The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor. 4.6.4 Indian GCP 3.3.6. Investigational Product(s) Investigator has the primary responsibility for investigational product(s) accountability at the study site(s). Investigator should maintain records of the products delivery to the study site, the inventory at the site, the use by each subject, and the return to the sponsor or the alternative disposal of the unused product(s). These records should include dates, quantities, batch / serial numbers, expiry dates if applicable, and the unique code number assigned to the investigational product packs and study subjects. Investigator should maintain records that describe that the subjects were provided the dosage specified by the protocol and reconcile all investigational products received from the sponsor. Investigator should ensure that the product(s) are stored under specified conditions and are used only in accordance with the approved protocol. The investigator should assign some or all of his / her duties for investigational products accountability at the study site(s) to his subordinate who is under the supervision of the investigator / institution. The investigator or subordinate should explain the correct use of the product(s) to each subject and should check at intervals appropriate for the study that each subject is following the instructions properly. The person who carries them out should document such periodic checks. Is there any comprehensive guide for how to start a CRO in India, its regulations? J. Vijayakumar At present, there is no formal guideline for setting up a CRO. In Jan 2011, CDSCO has issued a draft Schedule Y1 guidance for CRO registration. Some of the requirements for the CRO are: Should under the charge of a person who is responsible for the overall activities of the organization Have competent persons who are thoroughly familiar with the investigational product(s), the protocol, written informed consent forms or other information provided to the subjects, the standard operative procedures by the sponsors, GCP guidelines and other rules applicable to the

conduct of clinical trials. Have adequate resources, qualified and trained staff for oversight of clinical trials. Trial related duties and functions transferred to and assumed by the CRO specified in writing and properly quantified. Ensure that the trials are adequately monitored and the trial related responsibilities transferred to it, partially or fully, by the sponsor are discharged effectively and efficiently Implement quality assurance and quality control as per standard operative procedures designed for the purpose Maintain complete data, documentations and other related records accurately. Ensure that the investigator(s) received all documents and trial related supplies needed to conduct the trial properly. Have education programmes to help its investigators to carry out the research studies as per guidelines and regulations applicable to such trials. Training will include protocol adherence, GCP guidelines, informed consent process, and investigators responsibilities for GCP compliance. All records (written documents, electronics, magnetic or optical records, scans, etc.) such as protocols, approvals from the Central Drugs Standard Control Organization (CDSCO) and ethics committee, investigator(s) particulars, blank consent forms, monitor reports, audit certificates, relevant correspondence, reference ranges, completed and the final reports, shall be maintained.
What is retention quantity and retention period of investigational products (IPs) as per Indian guidelines? A D Asam Neither ICH nor Indian GCP recommend any duration for retention of samples. See below. However, as per Drugs and Cosmetics Act, for a manufactured batch, the duration is maximum of 3 years the date of manufacture ICH GCP 5.14.5(b) Maintain sufficient quantities of the investigational products used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are completed or as required by the applicable regulatory requirements, whichever represents the longer retention period.

Indian GCP 3.1.9. Supply, storage and handling of pharmaceutical products The sponsor should maintain sufficient samples from each batch and keep the record of their analyses and characteristics for reference, so that if necessary an independent laboratory may be able to recheck the same. Drugs and Cosmetics Act Conditions of license in Form 25 (l) the licensee shall maintain reference samples from each batch of the drugs manufactured by him in a quantity which is at least twice the quantity of the drug required to conduct all the tests performed on the batch. In case of drugs bearing an expiry date on the label, the reference samples shall be maintained for a period of three months beyond the date of expiry or potency. In case of drugs where no date of expiry of potency is specified on the label, the reference samples shall be maintained for a period of three years from the date of manufacture. Can a person play dual role in the EC quorum e.g. a legal expert can also represent lay person? Can an EC member (required for quorum), who could not attend the meeting, be sent documents for review and opinion collected? Rohit Prasad Lay person by definition is someone who is not an expert in any field. A lawyer cannot serve as lay person. Most ECs take a graduate / 12 standard pass person as lay person. Quorum requires physical presence of all members. An opinion sent by a member will not fulfill quorum. Which guideline should be followed for the conduct of observational and registry trials? Dr. Yashodha Madhu Volume 9A of the Rules governing medicinal products in the European Union guidelines on Pharmacovigilance for medicinal products for human use 7 company-sponsored post-authorisation safety studies covers non-interventional clinical studies. There are no specific guidelines for such studies. For epidemiology studies, ICMR 2006 ethical guidelines provide some guidance. Indian GCP recommends as follows: Phase IV Studies performed after marketing of the pharmaceutical product. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards

as applied in pre-marketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new pharmaceutical products. However, it is expected that the studies follow all scientific and ethical standards applicable to any human study. Can the chairperson of an EC play a dual role e.g. example chairperson as well as legal expert? Garima Singh Yes. A chair person could serve as legal person. In fact some ECs select a retired judge to serve as the chairperson. For doing a patch test study of a cosmeceutical, do we need approval of local regulatory authorities. In case the cosmeceutical is a US based product, and the sponsor wants to conduct the test on Indian volunteers, what will be the regulatory scenario in that case? Deepti Goel It would depend on what is the final indication for cosmeceutical. If the indication overlaps with definition of a drug, you need DCGI permission. As per Drugs and Cosmetics Act, drug includes all medicines for internal or external use of human beings or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings. Even if it does not meet definition of drug/new drug, in the current scenario, it is advisable to take DCGI permission for such studies. Kindly let me know if a person, who is graduate in arts and working in the hospital as an administrator and even assisting nursing staff, can he/she be assigned as site coordinator for clinical research? Dr. Manoj Yadav The role of clinical research coordinator covers several tasks which require background of medicine/pharmacy/other life sciences e.g. consent process, screening of subjects, completion of CRF, entries in SD, communication with subjects, coordination with EC and labs, facilitation of monitoring. GCP requires documentation of qualifications and training for all these functions. An arts graduate cannot do all these functions.

What are the regulatory requirements for marketing a new drug in India?

Ashish Chandra In June 2011, CDSCO released Guidance for Industry on Approval of Clinical Trials & New Drugs to specify the general requirements for approval of clinical trial and different categories of new drugs and the procedure for review of technical dossiers of such applications by CDSCO under Rule 122 A, 122B, 122DA, 122DAA,122E and Schedule Y of Drugs and Cosmetics Rules. The categories are as follows:

New Chemical Entity (NCE) developed in India as an IND and not marketed anywhere in world NCE approved and marketed in other countries not approved in India NCE being developed in other countries and not marketed anywhere in world A drug already approved - New claims New Indication New Dosage Form/ New Route of Administration Modified Release Dosage Form Fixed Dose Combination Already Approved New Drug

The number of study subjects and sites to be involved in the conduct of clinical trial will depend upon the nature and objective of the study. Phase I clinical trials should usually be carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects. These may be carried out at one or two centres. At least 2 subjects should be used on each dose. Phase II clinical trials should normally be carried out on 10-12 patients at each dose level. These studies should usually be carried out at 3-4 centres by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety. If the drug is already approved/marketed in other countries, phase III data should generally be obtained on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug, in Indian patients when used as recommended in the product monograph for the claims made. If the drug is a new drug substance discovered in India and not marketed in any other country, phase III data should be obtained on at least 500 patients distributed over 1015 centres. If an ethics committee is being shut down in the middle of an ongoing trial, can the site which has taken approval from that committee transfer to a new committee? in this scenario what are the regulatory guidelines? Naveed Mirza Yes. However, you need to have documentation to support this change. If the site is in an institute, you will need to have an official letter from site administration that 1)

the EC has stopped working 2) The site will accept jurisdiction of an external - Institutional Or independent EC. 3) External - Institutional or independent EC should accept the responsibility of the site. 4) You will have to formally approach the new EC, which should review the proposal in their official meeting and give EC approval. 5) You need to notify DCGI office about the change of EC. No new patients can be recruited till the whole process of EC approval from an external EC is obtained. In the site is a private clinic, you will need a letter from the EC that it has stopped working and items 2-5 from above. Please note as per DCGI's current guidelines, the EC has to be from the same location where the site is. If a pharma company wants to do a phase IV study with more number of subjects with lab tests, but for the same indication, same dosage and age group, then is DCGI approval needed or just a notification to DCGI is enough? Dr Nitin Kulkarni In recent times, DCGI office has noticed that companies are doing phase IV trials with designs similar to phase III studies, which have inclusion/exclusion criteria, objectives, investigations and end points. DCGI has been concerned about safety of subjects in such studies. Hence, DCGI office expects the sponsor to obtain permission for such trials from CDSCO. Can one sub investigator work for two investigators at different sites for the same study? Dr Nitin Kulkarni

Yes. He can work at two different sites. His name should be in the delegation log /FDA 1572 for both the sites. A study has begun and subjects are enrolled in the study at a few sites. When few more sites are added later, one of the ECs finds a fault/finding in ICF and asks to implement the change. Can we continue enrolling patients with the old ICF, where the study is ongoing and take re-consent after the new version is approved or do we have to stop screening at these sites? Dr Nitin Kulkarni It depends on what error the EC found and what is the change recommended. If the change affects/impacts, patient's rights, safety and well-being, then screening/recruitment should be suspended till the amended ICF is approved. During the trial, if site do not obtain consent to the amended ICF, will it be considered as a protocol deviation? After it was realized, subject was called over telephone and informed about the changes in the ICF and the same was documented in the source with reasons to why it was not obtained during the patient visit.

Gajjela Praveen Failure to obtain consent on amended ICF is a critical and serious protocol violation. It is not enough to call the subject on telephone and document in source. The site has to request the subject to visit the site to complete the consent process for the amended ICF. Please see an excerpt from FDA warning letter. As per the letter dated July 14, 2004, sent by your site to the IRB, you provided information that the use of was associated with the risk of serious confusion that had been identified in 23 other individuals, and that based on this possible serious adverse event, the informed consent document was being revised. We note that following notification of the IRBs approval of this revised consent form in a July 27, 2004 letter, your site failed to re-consent the 6 subjects, who were enrolled prior to the date of the approval of the revised informed consent document and who were still participating in the study. As a result of this failure, those subjects were not provided with an adequate description of the reasonably foreseeable risks of participating in the study. If the causality of an AE, that occurs during a BE study, (which is not listed under side effects in the reference drug label) is judged as related to the drug by the investigator of the BE study, does the generic drug label get updated with this new AE or it just has to match the reference drug label? Is it true that the generic drug label should match the reference label in all respects? Nanda Kumari P The side effects described in the reference package insert are side effects for which a causal relationship exists between the drug and the side effect. These are Adverse Drug Reactions (ADRs) i.e. adverse events for which causality is established. These depend on the chemical nature/structure of the reference drug. As generic and reference drug are both identical chemically/structurally, the side effect profile of generic should match the side effect profile of reference drug. The drug label side effect section is derived from clinical trials. As BE studies are usually single dose in healthy volunteers, it is difficult to be sure about the causality of AE. However, if the generic drug is studied a large trial of 500-1000 patients and if new ADRs are reported (ADRs not reported with reference drug label), then regulatory authorities will ask the new side effects to be added to all labels - generic as well as reference. Hence, generic drug labels usually follow the reference drug labels. Is there any guideline in India on protocol violations? How are these classified? Is the protocol violation notified by sponsor? Ashish Chavda There is no guideline in India on protocol deviation/violation. US FDA has given following definition: Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and

investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical well-being of the subject (21 CFR 812.35(a) (2)), and generally communicated to FDA. Protocol deviation is also used to refer to any other, unplanned, instance(s) of protocol noncompliance. EFGCP Audit Working Party 2001

Protocol Violation: serious non-compliance - may lead to exclusion of patients from eligibility analysis and/or their discontinuation from the study Protocol Deviation: less serious non-compliance - may not render a patient ineligible Norman M. Goldfarb J of Clinical Research Best Practices Nov 2005 Protocol Deviation. A protocol deviation occurs when, without significant consequences, the activities on a study diverge from the IRB-approved protocol, e.g., missing a visit window because the subject is travelling. Not as serious as a protocol violation. Protocol Violation. A divergence from the protocol that materially (a) reduces the quality or completeness of the data, (b) makes the ICF inaccurate, or (c) impacts a subjects safety, rights or welfare. Examples of protocol violations may include: Inadequate or delinquent informed consent Inclusion/exclusion criteria not met Unreported SAEs Improper breaking of the blind Use of prohibited medication Incorrect or missing tests Mishandled samples Multiple visits missed or outside permissible windows Materially inadequate record-keeping Intentional deviation from protocol, GCP or regulations by study personnel Subject repeated non-compliance with study requirements